The family Arenaviridae consists of a single genus (Arenavirus) that includes several viruses. Rodents are the primary reservoirs of Arenaviruses, and human infection is thought to occur by contact with infectious rodent excreta. Two groups of Arenaviruses are currently recognized. The Old World group (lymphocytic choriomeningitis (LCM)-Lassa complex) includes viruses indigenous to Africa and the ubiquitous LCM virus. The New World group (Tacaribe complex) includes viruses indigenous to the Americas. Several Arenaviruses are associated with severe hemorrhagic disease in humans. Lassa virus (from the Old World group) is responsible for Lassa hemorrhagic fever, while four viruses from the New World group (all from Clade B) cause severe hemorrhagic fever in humans. Those viruses are Juní virus, which is responsible for Argentine hemorrhagic fever; Machupo virus, which is responsible for Bolivian hemorrhagic fever; Guanarito virus, which is responsible for Venezuelan hemorrhagic fever; and Sabiá virus, which was isolated from a fatal case of hemorrhagic fever in Brazil. It is estimated that Lassa virus causes 100,000-300,000 infections and approximately 5,000 deaths annually. So far an estimated 30,000 confirmed cases of Juní infections have been documented, while about 2,000 of Machupo, 200 of Guanarito and only 2 of Sabiá.
Recent concerns over the use of Arenaviruses as biological weapons have underscored the necessity of developing small-molecule therapeutics that target these viruses. These Arenaviruses are a serious biowarfare threat because of: (i) their high disease morbidity and mortality (case fatality rates of 15-30%); (ii) their ease of dissemination and aerosol transmissibility; and (iii) the ease of obtaining and producing large quantities of these viruses.
Currently, there are no specific treatments approved for use against Arenavirus hemorrhagic fevers. Present disease management consists of general supportive care—monitoring and correcting fluid, electrolyte and osmotic imbalances and treating hemorrhage with clotting factor or platelet replacement. Convalescent immune serum therapy may be effective in treating cases of Juní and Machupo virus disease, but the availability of such serum is extremely limited.
Ribavirin, a nucleoside analog, has been used with some success in Lassa fever patients. In small trials, intravenous ribavirin given to patients within the first 6 days after development of fever decreased mortality from 76% to 9%. A controlled trial of 18 patients with Argentine hemorrhagic fever resulted in 13% mortality in treated patients, compared with 40% mortality in untreated patients. However, Ribavirin therapy is associated with adverse effects, including a dose-related, reversible hemolytic anemia, and also has demonstrated teratogenicity and embryo lethality in several animal species. It is therefore classified as a pregnancy category X drug, contraindicated during pregnancy. Intravenous ribavirin is available in limited supplies in the U.S. for compassionate use under an IND application. The dosing regimen for ribavirin therapy that has been used in cases of Lassa fever consists of an initial 30 mg/kg intravenous (IV) loading dose, followed by 16 mg/kg IV every 6 hours for 4 days; then 8 mg/kg IV every 8 hours for 6 days (total treatment time 10 days). The cost of treatment for an adult male is approximately $800. The attributes of ribavirin make it less than ideal for the treatment of Arenavirus hemorrhagic fevers.
A number of in vitro inhibitors of Arenavirus replication have been reported in the literature including phenothiazines, trifluoroperazine and chlorpromazine amantadine brassinosteroids, and actinomycin D. The anti-Arenavirus activities of these compounds are generally weak and non-specific.
The only Arenavirus hemorrhagic fever for which studies have been undertaken toward development of a vaccine has been Argentine hemorrhagic fever (AHF) caused by Juní virus. A live-attenuated vaccine, called Candid 1, has been evaluated in controlled trials among agricultural workers in AHF-endemic areas, where it appeared to reduce the number of reported AHF cases with no serious side effects. It is not known if the Candid 1 vaccine would be useful against other Arenavirus hemorrhagic fevers and this vaccine is not available in the United States of America.
Based on these data, new therapies and preventives are clearly needed for infections and diseases caused by Arenavirus infection.
All human pathogenic Arenaviruses from the New World group causing hemorrhagic fever are from the Clade B. These human pathogen viruses require manipulation under high-level containment (BSL-4). However, Amapari and Tacaribe viruses, which are also from Clade B, can be grown in tissue culture under BSL-2 (low-level) containment. Working under low-level containment makes experimentation easier and safer with these viruses. While Amapari virus produces low cytopathic effect, Tacaribe virus can be grown readily in cell culture and produce robust CPE in 4 to 6 days. Since this CPE is directly related to viral replication, compounds that inhibit virus replication in cell culture can be identified readily as conferring protection from virus-induced CPE (although it is theoretically possible to inhibit CPE without inhibiting virus replication). Moreover, compounds having identified activity against Tacaribe virus will also likely be active against Arenavirus human pathogen causing hemorrhagic fever (Juní, Machupo, Guanarito and Sabiá) given the high degree of homology (around 70% identity for all 4 proteins of Tacaribe virus compared to Juní virus, with long stretch of protein with perfect identity) between these viruses.